Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

Abstract

The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.

Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice

“…62 56 Bivalent Nanobody-Fc Fusions Bind to RBD Natural Variants and Neutralize the SARS-CoV-2 D614G N501Y Virus. The four lead nanobodies were fused to the Fc domain of human IgG1 to allow bivalent binding and prevent rapid clearance in vivo.…”

“…The landscape of initial human antibody generation to SARS-CoV-2 RBD has been extensively mapped during the course of the pandemic (11,(53)(54)(55)(56)(57)(58)(59), defining several preferred immunoglobulin heavy chain variable region (IGHV) gene usages and public clonotypes as well as rarer individual epitopes. Preferred gene usages include IGHV3-53/66, IGHV 1 to 2, and IGHV1-58*01 paired with IGKV3-20*01 (53)(54)(55).…”

“…IGHV3-53/66 antibodies bind in one of two modes on the RBD, defined as binding mode 1 and 2 (56). Binding mode 1 antibodies, including B38 (60), recognize residues including K417 and Y489; some additionally contact N501 but do not interact with E484 or the WNb 2 contact regions 351 and 446 to 449.…”

Diverse immunoglobulin gene usage and convergent epitope targeting in neutralizing antibody responses to SARS-CoV-2

“…More variants are emerging, including B.1.1.7 from the UK, B.1.351 from South Africa, P.1 from Brazil, and B.1.427/429 in California. Some of the mutations from these variants have been shown to reduce neutralization activity of monoclonal antibodies and sera from vaccinees and convalescent patients (Planas et al, 2021;Wang et al, 2021;Yuan et al, 2021a;Zhou et al, 2021).…”

The pivotal roles of the host immune response in the fine-tuning the infection and the development of the vaccines for SARS-CoV-2

“…Several SARS-CoV-2 mutants were reported recently in many countries, especially the UK, South Africa, Brazil, and India. 109 , 110 These mutants have higher transmissibility and replication potential than the viruses reported in the early phase of the pandemic. 109, 110 Most of these mutations occur within the RBD of the S protein of the virus.…”